110.Berod, A.A., et al. The role of American Society of
Anesthesiologists scores in predicting urothelial carcinoma of the upper urinary tract outcome after radical
nephroureterectomy: results from a national multi-institutional collaborative study. BJU Int, 2012. 110:
E1035.

166.Favaretto, R.L., et al. Comparison between
laparoscopic and open radical nephroureterectomy in a contemporary group of patients: are recurrence and
disease-specific survival associated with surgical technique? Eur Urol, 2010. 58: 645.

200.Moschini, M., et al. Impact of Primary Tumor Location
on Survival from the European Organization for the Research and Treatment of Cancer Advanced Urothelial
Cancer Studies. J Urol, 2018. 199: 1149.

It must be emphasised that clinical guidelines present the best
evidence available to the experts but following guideline recommendations will not necessarily
result in the best outcome. Guidelines can never replace clinical expertise when making treatment
decisions for individual patients, but rather help to focus decisions - also taking personal values
and preferences/individual circumstances of patients into account.
Guidelines are not mandates and do not purport to be a legal standard of care.

1.2.Panel composition

The European Association of Urology (EAU) Guidelines Panel on NMIBC consists of an
international multidisciplinary group of clinicians, including urologists, uro-oncologists, a
radiologist, a pathologist and a statistician. Members of this panel have been selected based on
their expertise and to represent the professionals treating patients suspected of harbouring
urothelial carcinoma. All experts involved in the production of this document have submitted
potential conflict of interest statements, which can be viewed on the EAU website Uroweb: https://uroweb.org/guideline/upper-urinary-tract-urothelial-cell-carcinoma/.

1.3.Available publications

A quick reference document (Pocket guidelines) is available in print and as an app
for iOS and Android devices, presenting the main findings of the UTUC Guidelines. These are abridged
versions which may require consultation together with the full text version. Several scientific
publications are available as are a number of translations of all versions of the EAU UTUC
Guidelines, the most recent scientific summary was published in 2018 [4].
All documents are accessible through the EAU website Uroweb: http://uroweb.org/guideline/upper-urinary-tract-urothelial-cell-carcinoma/.

1.4.Publication history & summary of changes

The first EAU Guidelines on UTUC were published in 2011. The 2019 EAU UTUC
Guidelines present a limited update of the 2018 version.

1.4.1.Summary of changes

The literature for the complete document has been assessed and updated, whenever
relevant. Conclusions and recommendations have been rephrased and added to throughout the current
document.

Key changes for the 2019 print:

Section 3.2 – Risk factors, has been expanded

Section 4.4 – Future developments, was added

Section 5.6 - Summary of evidence and guidelines for the diagnosis of urothelial carcinoma of
the upper urinary tract - two recommendations were added.

5.6 Summary of evidence and guidelines for the diagnosis of urothelial carcinoma
of the upper urinary tract

Recommendations

Strength
rating

Use CT for staging
the chest.

Strong

If CT is
contra-indicated, magnetic resonance imaging may be used for imaging the abdomen and
pelvis.

Strong

Section 7.2.2 – Metastasectomy, has been added

Section 7.2.3 – Systemic treatments, has been expanded to include immune checkpoint
inhibitors.

2.METHODS

2.1.Data identification

Standard procedure for EAU Guidelines includes an annual assessment of newly
published literature in the field to guide future updates. For the 2019 UTUC Guidelines, new and
relevant evidence has been identified, collated and appraised through a structured assessment of the
literature. The search was restricted to articles published between July 12th 2017 and June 20th
(Cochrane)/June 26th 2018 (Embase). Databases searched included
Pubmed, Ovid, EMBASE and both the Cochrane Central Register of Controlled Trials and the Cochrane
Database of Systematic Reviews. After deduplication, a total of 478 unique records were identified,
retrieved and screened for relevance.

Excluded from the search were basic research studies, case
series, reports and editorial comments. Only articles published in the English language, addressing
adults were included. The publications identified were mainly retrospective, including some large
multicentre studies. Owing to the scarcity of randomised data, articles were selected based on the
following criteria: evolution of concepts, intermediate- and long-term clinical outcomes, study
quality, and relevance. Older studies were only included if they were historically relevant. A
detailed search strategy is available online: http://uroweb.org/guideline/upper-urinary-tract-urothelial-cell-carcinoma/?type=appendices-publications.

For Chapters 3-6 (Epidemiology, Aetiology and Pathology, Staging and Classification
systems, Diagnosis and Prognosis) references used in this text are assessed according to their level of
evidence (LE) based on the 2009 Oxford Centre for Evidence-Based Medicine (CEBM) Levels of Evidence [5].
For the Disease Management and Follow-up chapters (Chapters 7 and 8) a system modified from the 2009
CEBM LEs has been used [5].

For each recommendation within the guidelines there is an
accompanying online strength rating form, based on a modified GRADE methodology [6,7].
These forms address a number of key elements, namely:

The overall quality of the evidence which exists for the commendation references used in this
text are graded according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence
(see above) [5];

the magnitude of the effect (individual or combined effects);

the certainty of the results (precision, consistency, heterogeneity and other statistical or
study related factors);

the balance between desirable and undesirable outcomes;

the impact of patient values and preferences on the intervention;

the certainty of those patient values and preferences.

These key elements are the basis which panels use to define the strength rating of
each recommendation. The strength of each recommendation is represented by the words ‘strong’ or
‘weak’. The strength of each recommendation is determined by the balance between desirable and
undesirable consequences of alternative management strategies, the quality of the evidence
(including certainty of estimates), and nature and variability of patient values and preferences [8].
The strength rating forms will be available online.

A list of Associations endorsing the EAU Guidelines can also be
viewed online at the above address.

2.2.Review

The UTUC Guidelines have been peer-reviewed prior to publication in 2016. The
summary paper published in 2018 was peer-reviewed prior to publication [4].

3.EPIDEMIOLOGY, AETIOLOGY AND PATHOLOGY

3.1.Epidemiology

Urothelial carcinomas (UCs) are the fourth most common tumours in developed
countries [9].
They can be located in the lower (bladder and urethra) or the upper (pyelocaliceal cavities and
ureter) urinary tract. Bladder tumours account for 90-95% of UCs and are the most common urinary
tract malignancy [1].
Upper urinary tract urothelial carcinomas are uncommon and account for only 5-10% of UCs [9,10]
with an estimated annual incidence in Western countries of almost two cases per 100,000 inhabitants.
This rate has risen in the past few decades as a result of improved detection and improved bladder
cancer survival [11].
Pyelocaliceal tumours are approximately twice as common as ureteral tumours whilst multifocal
tumours are found in 10-20% of cases. The presence of concomitant carcinoma in situ of the upper tract is between 11 and 36% [11].
In 17% of cases, concurrent bladder cancer is present [12]
whilst a prior history of bladder cancer is found in 41% of American men but in only 4% of Chinese
men
[13].
This, along with genetic and epigenetic factors, may explain why Asian patients present with more
advanced and higher grade disease compared to other ethnic groups [11].
Following treatment, recurrence in the bladder occurs in 22-47% of UTUC patients [14]
compared with 2-6% in the contralateral upper tract [15].

With regards to UTUC occuring following an initial diagnosis of
bladder cancer, a series of 82 patients treated with bacillus Calmette-Guérin (BCG) that had regular
upper tract imaging between years 1 and 3 showed a 13% incidence of UTUC, all of which were
asymptomatic [16]
whilst in another series of 307 patients without routine upper tract imaging the incidence was 25% [17].
More recently, a multicentre cohort study (n = 402) with a 50 month follow-up has demonstrated an
UTUC incidence of 7.5% in NMIBC receiving BCG with predictors being intravesical recurrence and
nonpapillary tumour at transurethral resection of the bladder [16].
Following radical cystectomy for MIBC, 3-5% of patients develop a metachronous UTUC.

Sixty percent of UTUCs are invasive at diagnosis compared with
15-25% of bladder tumours [18]
and 7% have metastasised [11].
Upper urinary tract urothelial carcinomas have a peak incidence in individuals aged 70-90 years and
are three times more common in men [19].

Familial/hereditary UTUCs are linked to hereditary nonpolyposis
colorectal carcinoma [20]
and these patients can be screened during a short interview (Figure 3.1) [21].
Patients identified at high risk for hereditary nonpolyposis colorectal carcinoma (HNPCC) syndrome
should undergo DNA sequencing for patient and family counselling [20,22].
In Lynch-related UTUC, immunohistochemistry analysis showed loss of protein expression corresponding
to the disease-predisposing MMR (mismatch repair) gene mutation in 98% of the samples (46% were
microsatellite instable and 54% microsatellite stable) [23].
The majority of tumours developing in MSH2 mutation carriers [24].

Figure 3.1: Selection of patients with UTUC for hereditary screening during
the first medical interview

3.2.Risk factors

A number of environmental factors have been implicated in the development of UTUC [25].
Published evidence in support of a role for these factors is not strong, with the exception of
smoking and aristolochic acid.

Tobacco exposure increases the relative risk of UTUC from 2.5 to
7.0
[26-28].
A large population-based study, including 229,251 relatives of case subjects and 1197,552 relatives
of matched control subjects, assessing familial clustering in relatives of urothelial carcinoma
patients, has demonstrated genetic or environmental roots independent of smoking-related behaviours.
With more than a 9% of the cohort being UTUC patients, clustering was not seen in upper tract
disease. This may suggest that the familial clustering of urothelial cancer is specific to lower
tract cancers [29,30].

In Taiwan, the presence of arsenic in drinking water has been
tentatively linked to UTUC [31].
Aristolochic acid, a nitrophenanthrene carboxylic acid produced by Aristolochia
plants, exerts multiple effects on the urinary system. Aristolochic acid irreversibly injures renal
proximal tubules resulting in chronic tubulointerstitial disease, while the mutagenic properties of
this chemical carcinogen lead predominantly to UTUC [32-34].
Aristolochic acid has been linked recently to bladder cancer, renal cell carcinoma, hepatocellular
carcinoma and intrahepatic cholangiocarcinoma [35].
Two routes of exposure to aristolochic acid are known: (i) environmental contamination of
agricultural products by Aristolochia plants, as reported for
Balkan endemic nephropathy [36];
and (ii) ingestion of Aristolochia-based herbal remedies [37,38].
Aristolochia herbs are used worldwide, especially in China and
Taiwan [34].
Following bioactivation, aristolochic acid reacts with genomic DNA to form
aristolactam-deoxyadenosine adducts [39];
these lesions persist for decades in target tissues, serving as robust biomarkers of exposure (9).
These adducts generate a unique mutational spectrum, characterized by A>T transversions located
predominately on the non-transcribed strand of DNA [35,40].
Fewer than 10% of individuals exposed to aristolochic acid develop UTUC [33],
supporting a role for genetic determinants in the aetiology of this disease.

Alcohol consumption may be an independent risk factor for UTUC. A large
case-control study (1,569 cases and 506,797 controls) has evidenced a significantly higher risk of
UTUC in ever-drinkers compared to never-drinkers (OR: 1.23; 95% CI: 1.08-1.40; p = 0.001). Compared
to never-drinkers, the risk threshold for UTUC was > 15 gr of alcohol/day. A dose-response was
observed [41].

Differences in the ability to counteract carcinogens may contribute to host
susceptibility to UTUC. Some genetic polymorphisms are associated with an increased risk of cancer
or faster disease progression that introduces variability in the inter-individual susceptibility to
the risk factors previously mentioned.

Upper urinary tract urothelial carcinomas may share some risk
factors and molecular pathways with bladder UC. So far, two UTUC-specific polymorphisms have been
reported [42].

3.3.Histology and classification

3.3.1.Histological types

Upper urinary tract urothelial carcinoma with pure non-urothelial histology is rare
[43,44]
but variants are present in approximately 25% of cases [45,46].
These variants correspond to high-grade tumours with worse prognosis compared with pure UC [47].
Squamous cell carcinoma of the upper urinary tract (UUT) represents < 10% of pyelocaliceal
tumours and is even rarer within the ureter. Squamous cell carcinoma of the urinary tract is often
assumed to be associated with chronic inflammatory diseases and infections arising from urolithiasis
[48,49].
Other variants, although rare, include sarcomatoid and urothelial carcinomas with inverted growth
[47].

However, collecting duct carcinomas, which may seem to share
similar characteristics with UCs, display a unique transcriptomic signature as a renal cell cancer
subtype, with a putative cell of origin in the distal convoluted tubules. Therefore, collecting duct carcinomas have to be considered as renal cell tumours [50].

4.STAGING AND CLASSIFICATION SYSTEMS

4.1.Classification

The classification and morphology of UTUC and bladder carcinoma are similar [1].
It is possible to distinguish between non-invasive papillary tumours (papillary urothelial tumours
of low malignant potential and low- and high-grade papillary UC) [51],
flat lesions (carcinoma in situ [CIS]), and invasive carcinoma.
As in bladder tumours, non-urothelial differentiation (i.e., histologic variants) confers an adverse
risk factor.

4.2.Tumour Node Metastasis staging

The tumour, node, metastasis (TNM) classification is shown in Table 1 [52].
The regional lymph nodes are the hilar and retroperitoneal nodes and, for the mid- and distal
ureter, the intrapelvine nodes. Laterality does not affect N classification. Renal pelvic pT3
subclassification may discriminate between microscopic infiltration of the renal parenchyma (pT3a)
and macroscopic infiltration or invasion of peripelvic adipose tissue (pT3b) [45,53,54].
pT3b UTUC has a higher risk of disease recurrence after radical nephroureterectomy (RNU) [45,53].

4.3.Tumour grade

Until 2004, the 1973 World Health Organisation (WHO) classification was used for
tumour grading and distinguished grades G1-G3 [55].
The 2004/2016 WHO classification distinguishes between non-invasive tumours: papillary urothelial
neoplasia of low malignant potential, and low- and high-grade carcinomas (low grade vs. high grade).
The current guidelines are based on the 2004/2016 WHO classification [55,56].

4.4.Future developments

A number of recent studies focussing on molecular classification have been able to
demonstrate genetically different groups of upper urinary tract urothelial cancer by evaluating DNA,
RNA and protein expression. Four molecular subtypes with distinct clinical behaviours were
identified, but, as yet, it is unclear whether these subtypes will respond differently to treatment
[57].

Tumour invades
adjacent organs or through the kidney into perinephric fat

N
- Regional lymph nodes

NX

Regional lymph
nodes cannot be assessed

N0

No regional lymph
node metastasis

N1

Metastasis in a
single lymph node 2 cm or less in the greatest dimension

N2

Metastasis in a
single lymph node more than 2 cm, or multiple lymph nodes

M
- Distant metastasis

M0

No distant
metastasis

M1

Distant
metastasis

5.DIAGNOSIS

5.1.Symptoms

The diagnosis of UTUC may be incidental or related to the evaluation of symptoms
that are generally limited. The most common symptom is visible or nonvisible haematuria (70-80%) [58,59].
Flank pain occurs in approximately 20% of cases, and a lumbar mass is present in approximately 10%
of patients [60,61].
Systemic symptoms (including anorexia, weight loss, malaise, fatigue, fever, night sweats, or cough)
associated with UTUC should prompt more rigorous metastatic evaluation; they confer a worse
prognosis [60,61].

5.2.Imaging

5.2.1.Computed tomography urography

Computed tomography (CT) urography has the highest diagnostic accuracy of the
available imaging techniques [62-65].
The sensitivity of CT urography for UTUC is 0.67–1.0 and specificity is 0.93–0.99 [66].

Rapid acquisition of thin sections allows high-resolution
isotropic images that can be viewed in multiple planes to assist with diagnosis without loss of
resolution. Epithelial “flat lesions” without mass effect or urothelial thickening are generally not
visible with CT.

The secondary sign of hydronephrosis is associated with advanced
disease and poor oncological outcome [60,67,68].
The presence of enlarged lymph nodes is highly predictive of metastases in UTUC [68].

5.2.2.Magnetic resonance urography

Magnetic resonance (MR) urography is indicated in patients who cannot undergo CT
urography, usually when radiation or iodinated contrast media are contraindicated [69].
The sensitivity of MR urography is 0.75 after contrast injection for tumours < 2 cm [69].
The use of MR urography with gadolinium-based contrast media should be limited in patients with
severe renal impairment (< 30 mL/min creatinine clearance), due to the risk of nephrogenic
systemic fibrosis. Computed tomography urography is generally preferred to MR urography for
diagnosing and staging UTUC.

5.3.Cystoscopy and urinary cytology

Abnormal cytology findings are suggestive of UTUC when bladder cystoscopy is
normal, provided no CIS in the bladder or prostatic urethra has been detected [1,70,71].
Cytology is less sensitive for UTUC than bladder tumours and should be performed in situ in the renal cavities [72].
Retrograde ureteropyelography remains an option to detect UTUCs [63,66,73].
Urinary cytology of the renal cavities and ureteral lumina is preferred before application of a
contrast agent for retrograde ureteropyelography because it may cause deterioration of cytological
specimens [67,73].
In a recent study, barbotage cytology detected up to 91% of cancers, being as effective as biopsy
histology [74].

The sensitivity of fluorescence in situ
hybridisation (FISH) for molecular abnormalities characteristic of UTUCs parallels its performance
in bladder cancer. However, its use may be limited by the preponderance of low-grade recurrent
disease in the population undergoing surveillance and kidney-sparing therapy for UTUCs [75,76].
Therefore, FISH has limited value in the surveillance of UTUCs [75,76].

5.4.Diagnostic ureteroscopy

Flexible ureteroscopy (URS) is used to visualise the ureter, renal pelvis and
collecting system and for biopsy of suspicious lesions. Ureteroscopic biopsies can determine tumour
grade in 90% of cases with a low false-negative rate, regardless of sample size [77].
Undergrading may occur following diagnostic biopsy, making intensive follow-up necessary if
kidney-sparing treatment is chosen [78].
Ureteroscopy also facilitates selective ureteral sampling for cytology in situ [73,79,80].
Stage assessment using ureteroscopic biopsy is notoriously difficult.

Flexible ureteroscopy is particularly useful in diagnostic
uncertainty, if kidney-sparing treatment is considered, or in patients with a solitary kidney.
Additional information can be provided by ureteroscopy with or without biopsy. Combining
ureteroscopic biopsy grade, imaging findings such as hydronephrosis, and urinary cytology may help
in the decision-making process between RNU and kidney-sparing therapy [80,81].
However, recent studies suggest a higher rate of intravesical recurrence after RNU in patients who
underwent diagnostic URS preoperatively [82,83].

Technical developments in flexible ureteroscopes and the use of novel imaging
techniques improve visualisation and diagnosis of flat lesions [84].
Narrow-band imaging is a promising technique, but results are preliminary [81,85,86].
Optical coherence tomography and confocal laser endomicroscopy (Cellvizio®) have been used in vivo to
evaluate tumour grade and/or for staging purposes, with a promising correlation with definitive
histology in high-grade UTUC [87,88].
Recommendations for the diagnosis of UTUC are listed in Section 5.6.

5.5.Distant metastasis

Prior to any curative treatment, it is essential to evaluate the presence of
distant metastases. Computed tomography and MRI are the diagnostic techniques of choice to detect
lung [89]
and liver metastases [90],
respectively.

5.6.Summary of evidence and guidelines for the diagnosis
of urothelial carcinoma of the upper urinary tract

Use diagnostic
ureteroscopy and biopsy only if the result will influence the type of treatment.

Strong

Use CT for staging
the chest.

Strong

If CT is
contra-indicated, magnetic resonance imaging may be used for imaging the abdomen and
pelvis.

Strong

6.PROGNOSIS

6.1.Prognostic factors

Upper urinary tract urothelial carcinomas that invade the muscle wall usually have
a very poor prognosis. The 5-year specific survival is < 50% for pT2/pT3 and < 10% for pT4 [85,91,92].
The main prognostic factors are briefly listed in the text. Figure 6.1 shows an exhaustive list.

6.2.Pre-operative factors

6.2.1.Age and gender

Age is one of the most important demographic predictors of survival in UTUC [93].
Older age at the time of RNU is independently associated with decreased cancer-specific survival [54,92,94]
(LE: 3). Many elderly patients can be cured with RNU [95],
suggesting that age alone is an inadequate indicator of outcome [94,95].
Despite its association with survival, age alone should not prevent a potentially curable approach.
Gender is no longer considered an independent prognostic factor influencing UTUC mortality [19,68,92,96].

6.2.2.Ethnicity

One multicentre study did not show any difference in outcome between races [97],
but population-based studies have indicated that African-American patients have worse outcomes than
other ethnicities (LE: 3). Another study has underlined differences between Chinese and
American patients at presentation (risk factor, disease characteristics and predictors of adverse
oncologic outcomes) [13].

6.2.3.Tobacco consumption

Being a smoker at diagnosis increases the risk for disease recurrence and mortality
after RNU [98,99]
and recurrence within the bladder [100]
(LE: 3). There is a close relationship between tobacco consumption and prognosis; smoking
cessation improves cancer control.

6.2.4.Tumour location

Initial location of the UTUC is a prognostic factor in some studies [101,102]
(LE: 3). After adjustment for the effect of tumour stage, patients with ureteral and/or
multifocal tumours seem to have a worse prognosis than patients diagnosed with renal pelvic tumours
[92,101-105].

6.2.5.Surgical delay

A delay between diagnosis of an invasive tumour and its removal may increase the
risk of disease progression. Once a decision regarding RNU has been made, the procedure should be carried out
within twelve weeks, when possible [106-109]
(LE: 3).

6.3.Post-operative factors

6.3.1.Tumour stage and grade

6.3.2.Lymph node involvement

Lymph node metastases and extranodal extension are powerful predictors of survival
outcomes in UTUC [116].
Lymph node dissection (LND) performed at the time of RNU allows for optimal tumour staging, but its
curative role remains debated [117,118]
(LE: 3).

6.3.3.Lymphovascular invasion

Lymphovascular invasion is present in approximately 20% of UTUCs and is an
independent predictor of survival [119,120].
Lymphovascular invasion status should be specifically reported in the pathological reports of all
UTUC specimens [119,121]
(LE: 3).

6.3.4.Surgical margins

Positive soft tissue surgical margin after RNU is a significant factor for
developing disease recurrence. Pathologists should look for and report positive margins at the level
of ureteral transection, bladder cuff, and around the tumour if T > 2 [122]
(LE: 3).

6.3.5.Pathological factors

Extensive tumour necrosis (> 10% of the tumour area) is an independent
prognostic predictor in patients who undergo RNU [123,124]
(LE: 3). The architecture of UTUC is also a strong prognosticator with sessile growth pattern
being associated with worse outcome [125,126]
(LE: 3). Concomitant CIS in organ-confined UTUC and a history of bladder CIS are associated
with a higher risk of recurrence and cancer-specific mortality [127,128]
(LE: 3).

6.4.Molecular markers

Several studies have investigated the prognostic impact of molecular markers
related to cell adhesion (E-cadherin [129]
and CD24), cell differentiation (Snail and human epidermal growth factor receptor HER-2 [130]),
angiogenesis (hypoxia inducible factor 1α and metalloproteinases), cell
proliferation (Ki-67), epithelial-mesenchymal transition (Snail), mitosis (Aurora A), apoptosis
(Bcl-2 and survivin), vascular invasion (RON), and c-met protein (MET) [92,131].
Microsatellite instability is an independent molecular prognostic marker [132].
Microsatellite instability typing can help detect germline mutations and hereditary cancers [20].
Interestingly, there is a prognostic value of PD-1 and PDL-1 expression in patients with high-grade
UTUC [133].
Because of the rarity of UTUC, the main limitations of molecular studies are their retrospective
design and, for most studies, small sample size. None of the markers have yet fulfilled the criteria
necessary to support their introduction in daily clinical decision making.

6.5.Predictive tools

Accurate predictive tools are rare for UTUC. There are two models in the
pre-operative setting: one for predicting LND of locally advanced cancer that could guide the
decision to perform an LND as well as the extent of LND at the time of RNU [134],
and a second model for the selection of non-organ-confined UTUC which is likely to benefit from RNU
[135].
Five nomograms are available; four predict survival rates, post-operatively, based on standard
pathological features [136-140].
A fifth nomogram, based on only four variables, shows a higher prognostic accuracy and risk
stratification in patients with high-grade UTUC [141].

6.5.1.Bladder recurrence

A recent meta-analysis of available data has identified significant predictors of
bladder recurrence after RNU [142]
(LE: 3). Three categories of predictors of increased risk for bladder recurrence were
identified:

In addition, the use of diagnostic ureteroscopy has been associated with a higher
risk of developing bladder recurrence after RNU [82,83]
(LE: 3).

6.6.Risk stratification

As tumour stage is difficult to assert clinically in UTUC, it is useful to “risk
stratify” UTUC between low- and high-risk tumours to identify those patients who are more suitable
for kidney-sparing treatment rather than radical extirpative surgery [143,144]
(Figure 6.2).

Use microsatellite
instability as an independent molecular prognostic marker to help detect germline mutations
and hereditary cancers.

Weak

7.DISEASE MANAGEMENT

7.1.Localised disease

7.1.1.Kidney-sparing surgery

Kidney-sparing surgery for low-risk UTUC reduces the morbidity associated with
radical surgery, without compromising oncological outcomes and kidney function, as stated in a
systematic review from the EAU Non-muscle-invasive Bladder Cancer Guidelines Panel [145].
In low-risk cancers, it is the preferred approach with survival being similar after kidney-sparing
surgery vs. RNU [145].
This option should therefore be discussed in all low-risk cases, irrespective of the status of the
contralateral kidney. In addition, it can also be considered in select patients with serious renal
insufficiency or solitary kidney (LE: 3). Recommendations for kidney-sparing management of UTUC
are listed in Section 7.1.1.1.

Offer kidney-sparing
management to patients with solitary kidney and/or impaired renal function, providing that
it will not compromise survival. This decision will have to be made on a case-by-case basis
with the patient.

Strong

Use a laser for
endoscopic management of upper tract urothelial carcinoma.

Weak

7.1.1.2.Ureteroscopy

Endoscopic ablation can be considered in patients with clinically low-risk cancer
in the following situations [146,147]:

The patient is informed of the need for early (second look) [149],
closer, more stringent, surveillance;

Complete tumour resection or destruction can be achieved.

Nevertheless, a risk of understaging and undergrading remains with endoscopic
management [150].

7.1.1.3.Percutaneous access

Percutaneous management can be considered for low-risk UTUC in the renal pelvis [147,151]
(LE: 3). This may be offered for low-risk tumours in the lower caliceal system that are
inaccessible or difficult to manage by flexible ureteroscopy. However, this approach is being used
less due to the availability of improved endoscopic tools such as distal-tip deflection of recent
ureteroscopes [147,151].
A risk of tumour seeding remains with a percutaneous access.

7.1.1.4.Segmental ureteral resection

Segmental ureteral resection with wide margins provides adequate pathological
specimens for staging and grading while preserving the ipsilateral kidney. Lymphadenectomy can also
be performed during segmental ureteral resection [145].

Complete distal ureterectomy with neocystostomy are indicated for
low-risk tumours in the distal ureter that cannot be removed completely endoscopically and for
high-risk tumours when kidney-sparing surgery for renal function preservation is necessary [152-154]
(LE: 3).

Segmental resection of the iliac and lumbar ureter is associated
with higher failure rates than for the distal pelvic ureter [55,152,153]
(LE: 3).

Partial pyelectomy or partial nephrectomy is extremely rarely
indicated. Open resection of tumours of the renal pelvis or calices has almost disappeared.

7.1.1.5.Upper urinary tract instillation of topical
agents

The antegrade instillation of BCG vaccine or mitomycin C in the UUT by percutaneous
nephrostomy via a three-valve system open at 20 cm (after complete tumour eradication) is feasible
after kidney-sparing management [128,155]
(LE: 3). Retrograde instillation through a ureteric stent is also used, but it can be dangerous
due to possible ureteric obstruction and consecutive pyelovenous influx during
instillation/perfusion. The reflux obtained from a double-J stent has been used but this approach is
suboptimal because the drug often does not reach the renal pelvis [156-159].

7.1.2.Radical nephroureterectomy

7.1.2.1.Surgical approach

7.1.2.1.1.Open radical nephroureterectomy

Open RNU with bladder cuff excision is the standard for high-risk UTUC, regardless
of tumour location [18]
(LE: 3). Radical nephroureterectomy must comply with oncological principles, that is,
preventing tumour seeding by avoidance of entry into the urinary tract during resection [18].
Section 7.1.2.3 lists the recommendations for RNU.

Resection of the distal ureter and its orifice is performed
because there is a considerable risk of tumour recurrence in this area [142].
After removal of the proximal ureter, it is difficult to image or approach it by endoscopy. Removal
of the distal ureter and bladder cuff is beneficial after RNU [152,160].

Several techniques have been considered to simplify distal ureter
resection, including pluck technique, stripping, transurethral resection of the intramural ureter,
and intussusception. Except for ureteral stripping, none of these techniques is inferior to bladder cuff excision [15,161,162]
(LE: 3).

7.1.2.1.2.Laparoscopic
radical nephroureterectomy

Retroperitoneal metastatic dissemination and metastasis along the trocar pathway
following manipulation of large tumours in a pneumoperitoneal environment have been reported in a
few cases [163,164].
Several precautions may lower the risk of tumour spillage:

Avoid entering the
urinary tract.

Avoid direct contact between instruments and the tumour.

Laparoscopic RNU must take place in a closed system. Avoid morcellation of the tumour and use an
endobag for tumour extraction.

The kidney and ureter must be removed en bloc with the
bladder cuff.

Invasive or large (T3/T4 and/or N+/M+) tumours are contraindications for laparoscopic RNU as the
outcome is poorer compared to an open approach as stated in a systematic review by the EAU
Guidelines Panel [165].

Laparoscopic RNU is safe in experienced hands when adhering to strict oncological
principles. There is a tendency towards equivalent oncological outcomes after laparoscopic or open
RNU
[164,166-169]
(LE: 3). Only one prospective randomised study has shown that laparoscopic RNU is not inferior
to open RNU for non-invasive UTUC [170]
(LE: 2). Oncological outcomes after RNU have not changed significantly over the past three
decades despite staging and surgical refinements [171]
(LE: 3). A robot-assisted laparoscopic approach can be considered with recent data suggesting
oncologic equivalence with other approaches [172-174].

7.1.2.2.Lymph node dissection

The anatomic sites of lymph node drainage have not yet been clearly defined. The
use of an LND template is likely to have a greater impact on patient survival than the number of
removed lymph nodes [175].

Lymph node dissection appears to be unnecessary in cases of TaT1
UTUC because LN retrieval is reported in only 2.2% of T1 vs. 16% of pT2-4 tumours [116,176],
so it is used infrequently [177].
An increase in the probability of lymph node-positive disease is related to pT classification [118].
Lymph node dissection is performed according to an anatomical template-based approach [178].

Despite available studies evaluating templates to date, it is not
possible to standardise indication or extent of LND. Lymph node dissection can be achieved following
lymphatic drainage as follows: LND on the side of the affected ureter, retroperitoneal LND for
higher ureteral tumour, and/or tumour of the renal pelvis (i.e., right side: border vena cava or
right side of the aorta; and left side: border aorta) [116,117].

7.1.2.3.Summary of evidence and guidelines for
radical nephroureterectomy

Offer a
post-operative bladder instillation of chemotherapy to lower the intravesical recurrence
rate.

Strong

7.1.3.Perioperative chemotherapy as an adjunct to radical nephroureterectomy

7.1.3.1.Neoadjuvant chemotherapy

Several ongoing RCTs are currently accruing UTUC patients to assess the impact of
neoadjuvant chemotherapy before undergoing RNU. Although level I evidence is not available yet, in
high-risk patients, multimodal management has been associated with significant downstaging at
surgery and ultimately survival benefit as compared to RNU alone [179-181].
A recent study showed that benefit was predominantly seen in patients with locally advanced disease
[182].

7.1.3.2.Adjuvant chemotherapy

There are several platinum-based regimens [183],
but not all patients can receive adjuvant chemotherapy because of comorbidities and impaired renal
function after RNU. Particularly, the post-operative decrease in renal function may limit the use of
cisplatin-based adjuvant chemotherapy [184,185].

Available observational studies show heterogeneous results with
regard to the effectiveness of adjuvant chemotherapy [186-188].
Nonetheless, the largest study to date found an overall survival benefit for pT3/T4 and/or pN+ UTUC
[189]
(LE: 3). In addition, a recent RCT conducted in the UK demonstrated that the delivery of
adjuvant chemotherapy after RNU reduces the risk of recurrence by more than 50% as compared to
surgery alone. The toxicity profile appears to be acceptable [190].

7.1.4.Adjuvant Radiotherapy after radical nephroureterectomy

Adjuvant radiation therapy has been suggested to help control locoregional disease
after surgical removal. The data remains controversial and insufficient for conclusions [191-193].
Moreover, its additive value to chemotherapy remains to be tested [193].

7.1.5.Adjuvant bladder instillation

The rate of bladder recurrence after RNU for UTUC is 22-47%. Two prospective
randomised trials and a meta-analysis [194]
have demonstrated that a single post-operative dose of intravesical chemotherapy (mitomycin C,
pirarubicin) soon after surgery (between 2-10 days) reduces the risk of bladder tumour recurrence
within the first year post-RNU [195,196]
(LE: 2). Prior to instillation, consider a cystogram in case there are any concerns about
urinary extravasation.

Whilst there is no direct evidence supporting the use of intravesical instillation
of chemotherapy after kidney-sparing surgery, single-dose chemotherapy might be effective in that
setting as well (LE: 4). Management is outlined in Figures 7.1 and 7.2.

7.2.Metastatic disease

7.2.1.Radical nephroureterectomy

The role of RNU in the treatment of patients with metastatic UTUC has recently been
explored in several observational studies. Although evidence remains very limited, RNU may be
associated with cancer-specific [197]
and overall survival benefit in selected patients, especially those fit enough to receive
cisplatin-based chemotherapy [198].
Given the high risk of bias of the observational studies addressing RNU for metastatic UTUC,
indications for RNU in this setting should mainly be reserved for palliative patients, aimed at
controlling symptomatic disease [17,98]
(LE: 3).

7.2.2.Metastasectomy

There is no evidence supporting the role of metastasectomy in patients with
advanced disease. However, a recent report including both UTUC and bladder cancer patients,
suggested that resection of metastatic lesions could be safe and oncologically beneficial in highly
selected patients with a reasonable life expectancy [199].
In the absence of data from RCTs, patients should be evaluated on an individual basis.

7.2.3.Systemic treatments

Extrapolating from the bladder cancer literature and small, single-centre UTUC
studies, platinum-based combination chemotherapy – especially using cisplatin – might be efficacious
for first-line treatment of metastatic UTUC. A retrospective analysis of three RCTs showed that
primary tumour location had no impact on progression-free or overall survival in patients with
locally advanced or metastatic urothelial carcinoma treated with platinum-based combination
chemotherapy [200].

In addition, the role of immune checkpoint inhibitors such as
pembrolizumab [201]
and atezolizumab [202]
has recently been evaluated in the first-line setting for cisplatin-ineligible patients with
metastatic urothelial carcinoma. Although the vast majority of included patients had bladder cancer,
some UTUC-specific data showed that the objective response rate ranges between 22 and 39%.

Similar to the bladder cancer setting, second-line treatment of
metastatic UTUC remains challenging. In a post-hoc subgroup
analysis of metastatic/locally advanced UC, vinflunine was reported to be as effective as when used
in metastatic bladder cancer progressing after cisplatin-based chemotherapy [203].
More importantly, Rosenberg et al. demonstrated that
pembrolizumab could decrease the risk of death by almost 50% in UTUC patients who received prior
platinum-based chemotherapy, although these results were borderline significant. Interestingly,
atezolizumab was granted FDA approval as a second-line treatment option in patients with metastatic
urothelial carcinoma based on the results of a phase II study [204],
but the phase III study showed no significant difference in overall survival when compared to
salvage chemotherapy, although the safety profile was more favourable for atezolizumab [205].
Similar results were observed when analyses were restricted to the subgroup of patients with
metastatic UTUC only.

8.FOLLOW-UP

The risk of recurrence and death evolves during the follow-up period after surgery
[206].
Stringent follow-up (Section 8.1) is mandatory to detect metachronous bladder tumours (probability
increases over time [207]),
local recurrence, and distant metastases. Section 8.1 presents the summary of evidence and
recommendations for follow-up of UTUC.

Surveillance regimens are based on cystoscopy and urinary
cytology for > 5 years [12,14,15,142].
Bladder recurrence is not considered a distant recurrence. When kidney-sparing
surgery is performed, the ipsilateral UUT requires careful follow-up due to the high risk of disease
recurrence [148,208,209].
Despite endourological improvements, follow-up after kidney-sparing management is difficult and
frequent, and repeated endoscopic procedures are necessary. As done in bladder cancer, a second look
has been proposed after kidney-sparing surgery but is not yet routine practice [2,149].

8.1.Summary of evidence and guidelines for the follow-up
of UTUC

Summary of evidence

LE

Follow-up is more frequent and
more strict in patients who have undergone kidney-sparing treatment compared to radical
nephroureterectomy.

3

Recommendations

Strength
rating

After radical nephroureterectomy:

Low-risk tumours

Perform cystoscopy at
three months. If negative, perform subsequent cystoscopy nine months later and then yearly,
for five years.

Weak

High-risk tumours

Perform cystoscopy
and urinary cytology at three months. If negative, repeat subsequent cystoscopy and cytology every three months for a period of
two years, and every six months thereafter until five years, and then yearly.

Weak

Perform computed tomography (CT) urography and chest CT every six months for two years, and then yearly.

Weak

After kidney-sparing management:

Low-risk tumours

Perform cystoscopy
and CT urography at three and six months, and then yearly for five years.

Weak

Perform ureteroscopy
at three months.

Weak

High-risk tumours

Perform cystoscopy,
urinary cytology, CT urography and chest CT at three and six months, and then yearly.

Weak

Perform ureteroscopy
and urinary cytology in situ at three and six months.

110.Berod, A.A., et al. The role of
American Society of Anesthesiologists scores in predicting urothelial carcinoma of the upper urinary
tract outcome after radical nephroureterectomy: results from a national multi-institutional
collaborative study. BJU Int, 2012. 110: E1035.

166.Favaretto, R.L., et al.
Comparison between laparoscopic and open radical nephroureterectomy in a contemporary group of
patients: are recurrence and disease-specific survival associated with surgical technique? Eur Urol,
2010. 58: 645.

200.Moschini, M., et al. Impact of
Primary Tumor Location on Survival from the European Organization for the Research and Treatment of
Cancer Advanced Urothelial Cancer Studies. J Urol, 2018. 199: 1149.

10.CONFLICT OF INTEREST

All members of the Non-Muscle-Invasive Bladder Cancer Guidelines working panel have
provided disclosure statements on all relationships that they have that might be perceived to be a
potential source of a conflict of interest. This information is publically accessible through the
European Association of Urology website:http://uroweb.org/guideline/upper-urinary-tract-urothelial-cell-carcinoma/.

This guidelines document was developed with the financial support
of the European Association of Urology. No external sources of funding and support have been
involved. The EAU is a non-profit organisation, and funding is limited to administrative assistance
and travel and meeting expenses. No honoraria or other reimbursements have been provided.

11.CITATION INFORMATION

The format in which to cite the EAU Guidelines will vary depending on the style
guide of the journal in which the citation appears. Accordingly, the number of authors or whether,
for instance, to include the publisher, location, or an ISBN number may vary.

The compilation of the complete Guidelines should be referenced as:EAU Guidelines. Edn. presented at the EAU Annual Congress Barcelona 2019.
ISBN 978-94-92671-04-2.